EP1082961B1 - Sleep inducing agent comprising prostaglandin derivatives - Google Patents

Sleep inducing agent comprising prostaglandin derivatives Download PDF

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Publication number
EP1082961B1
EP1082961B1 EP99921249A EP99921249A EP1082961B1 EP 1082961 B1 EP1082961 B1 EP 1082961B1 EP 99921249 A EP99921249 A EP 99921249A EP 99921249 A EP99921249 A EP 99921249A EP 1082961 B1 EP1082961 B1 EP 1082961B1
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European Patent Office
Prior art keywords
group
sleep
cycloalkyl
formula
vinylene
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Expired - Lifetime
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EP99921249A
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German (de)
English (en)
French (fr)
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EP1082961A4 (en
EP1082961A1 (en
Inventor
Fumie Sato
Tohru Taisho Pharmaceutical Co. Ltd. Tanami
Kazuya Taisho Pharmaceutical Co. Ltd. Kameo
Kenji Taisho Pharmaceutical Co. Ltd. Yamada
Shigeru Taisho Pharmaceutical Co. Ltd. Okuyama
Naoya Taisho Pharmaceutical Co. Ltd. Ono
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof

Definitions

  • the present invention relates to the use of a prostaglandin derivative as an effective ingredient in the manufacture of a sleep-inducing preparation.
  • PG prostaglandin
  • PGs have been reported on the various central nervous actions and have been clarified as to the intracerebral content, biosynthesis, metabolic pathway, their intracerebral localizations and changes with growth or aging, and there has been taken an interest in the relation of PGs with sleep and wake.
  • PGD 2 has been known as an intracerebral humoral factor which controls the occurrence or maintenance of sleep, and it was made clear that the sleep induced by PGD 2 in monkeys is undistinguished from the spontaneous natural sleep in brain wave or behavior (Proc. Natl. Acad. Sci. USA, vol. 85, pp. 4082-4086 (1988)), therefore this compound is expected as a compound having a novel sleep-inducing action.
  • PGD 2 derivatives including PGD 2 are presently unpractical due to the problems concerning the effect and the stability as a drug.
  • EP 0 737 676 A relates to prostaglandin derivatives of the following formula wherein R 1 is hydrogen, alkyl or cycloalkyl, R 2 is cycloalkyl, methyl-cycloalkyl, cycloalkyl-alkyl, branched alkyl or branched alkenyl, X is halogen, A is an ethylene, Vinylene or ethynylene group. This document relates to the lowering of intra-ocular pressure as pharmaceutical effect.
  • EP 652 211 A discloses a prostaglandin derivative of the following formula wherein R represents a hydrogen atom or an alkyl group. These compounds exhibit activities for improving renal diseases, ischemic heart diseases and heart failure.
  • the prostaglandin derivative disclosed in JP 07 285 929 A has the following formula wherein X is halogen, R 1 is H or C 1-10 alkyl, and R 2 is for instance C 3-10 cycloalkyl. This document teaches the use of this prostaglandin derivative as intra-ocular pressure-lowering agent.
  • US 5,599,838 discloses a prostaglandin derivative represented by the formula: wherein X is halogen atom, R 1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R 2 is a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkylmethyl group having 4 to 10 carbon atoms or a cycloalkylethyl group having 5 to 12 carbon atoms, or a salt thereof, which has a lowering action of intraocular pressure and improving actions of renal diseases, ischemic heart diseases and heart failure.
  • the present inventors have found that the prostaglandin derivatives having a triple bond between the 13- and 14-positions represented by the following formula (I) have a characteristic sleep-inducing action, and thereby the present invention has been accomplished.
  • the present invention is directed to the use of a prostaglandin derivative represented by Formula (I) for the preparation of a medicament effective as sleep-inducing preparation : wherein X is a halogen atom, Y is a group represented by (CH 2 ) m , a cis-vinylene group or a phenylene group, Z is an ethylene group, a trans-vinylene group, OCH 2 or S(O) n CH 2 , R 1 is a C 3-10 cycloalkyl group, a C 3-10 cycloalkyl group substituted with C 1-4 alkyl group(s), a C 4-13 cycloalkylalkyl group, a C 5-10 alkyl group, a C 5-10 alkenyl group, a C 5-10 alkynyl group or a bridged cyclic hydrocarbon group, R 2 is a hydrogen atom, a C 1-10 alkyl group or a C 3-10 cycloalkyl group,
  • X is a chlorine atom or a bromine atom
  • Y is a group represented by (CH 2 ) m or a cis-vinylene group
  • Z is an ethylene group, a trans-vinylene group, OCH 2 or S(O) n CH 2
  • R 1 is a C 3-10 cycloalkyl group or a C 4-13 cycloalkylalkyl group
  • R 2 is a hydrogen atom or a C 1-10 alkyl group
  • m is an integer of 1 to 3
  • n is 0, 1 or 2.
  • the present invention is directed to the above use wherein, in the prostaglandin derivative represented by Formula (I) or a pharmaceutically acceptable salt thereof, X is a chlorine atom or a bromine atom, Y is a group represented by (CH 2 ) m or a cis-vinylene group, Z is OCH 2 , R 1 is a C 3-10 cycloalkyl group or a C 4-13 cycloalkylalkyl group, R 2 is a hydrogen atom or a C 1-10 alkyl group, and m is an integer of 1 to 3.
  • the present invention is directed to the above use wherein, in the prostaglandin derivative represented by Formula (I) or a pharmaceutically acceptable salt thereof, X is a chlorine atom or a bromine atom, Y is a group represented by (CH 2 ) m or a cis-vinylene group, Z is SCH 2 , R 1 is a C 3-10 cycloalkyl group or a C 4-13 cycloalkylalkyl group, R 2 is a hydrogen atom or a C 1-10 alkyl group, and m is an integer of 1 to 3.
  • the present invention is directed to the above use wherein, in the prostaglandin derivative represented by Formula (I), or a pharmaceutically acceptable salt thereof Y is a group represented by (CH 2 ) m , Z is SCH 2 , R 1 is a C 3-10 cycloalkyl group, R 2 is a hydrogen atom or a C 1-10 alkyl group, and m is an integer of 1 to 3.
  • the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • Examples of the C 3-10 cycloalkyl group are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
  • Examples of the C 3-10 cycloalkyl group substituted with C 1-4 alkyl group(s) are a methylcyclopropyl group, a methylcyclohexyl group and an ethylcyclohexyl group.
  • Examples of the C 4-13 cycloalkylalkyl group are a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclohexylmethyl group, a cyclohexylethyl group and a cycloheptylmethyl group.
  • the C 5-10 alkyl group refers to a straight or branched alkyl group, and examples thereof are a pentyl group, a hexyl group, a heptyl group, an octyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 2,4-dimethylpentyl group, a 2-ethylpentyl group, a 2-methylheptyl group, a 2-ethylhexyl group, a 2-propylpentyl group, a 2-propylhexyl group and a 2,6-dimethylheptyl group.
  • the C 5-10 alkenyl group refers to a straight or branched alkenyl group, and examples thereof are a 3-pentenyl group, a 4-hexenyl group, a 5-heptenyl group, a 4-methyl-3-pentenyl group, a 2,4-dimethylpentenyl group, a 6-methyl-5-heptenyl group and a 2,6-dimethyl-5-heptenyl group.
  • the C 5-10 alkynyl group refers to a straight or branched alkynyl group, and examples thereof are a 3-pentynyl group, a 3-hexynyl group, a 4-hexynyl group, a 1-methylpent-3-ynyl group, a 2-methylpent-3-ynyl group, a 1-methylhex-3-ynyl group and a 2-methylhex-3-ynyl group.
  • bridged cyclic hydrocarbon group examples include a bornyl group, a norbornyl group, an adamantyl group, a pinanyl group, a thujyl group, a caryl group and a camphanyl group.
  • the C 1-10 alkyl group for R 2 refers to a straight or branched alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a 2-ethylpropyl group, a hexyl group, an isohexyl group, a 1-ethylbutyl group, a heptyl group, an isoheptyl group, an octyl group, a nonyl group and a decyl group.
  • Examples of the pharmaceutically acceptable salt are salts with alkali metal (e.g. sodium or potassium), alkali earth metal (e.g. calcium or magnesium), ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, a tetraalkyl ammonium and tris(hydroxymethyl)aminomethane.
  • alkali metal e.g. sodium or potassium
  • alkali earth metal e.g. calcium or magnesium
  • ammonia methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, a tetraalkyl ammonium and tris(hydroxymethyl)aminomethane.
  • Y is preferably an ethylene group or cis-vinylene group
  • Z is preferably OCH 2 or SCH 2
  • R 1 is preferably a cycloalkyl group in Formula (I) of the prostaglandin derivatives as the effective ingredient.
  • Some of the compounds of Formula (I), according to the present invention, are known in WO94/02457, WO94/08959, Japanese Patent Kokai Hei-6-192218, Japanese Patent Kokai Hei-7-242622, Japanese Patent Kokai Hei-7-242623, Japanese Patent Kokai Hei-7-233144, Japanese Patent Kokai Hei-7-285929, Japanese Patent Kokai Hei-8-208599.
  • Japanese Patent Kokai Hei-7-233143 Japanese Patent Kokai Hei-9-286775, Japanese Patent Kokai Sho-58-8059, Japanese Patent Kohyo Sho-60-501813 and Japanese Patent Kohyo Sho-60-500787.
  • the compounds wherein Z is S(O)CH 2 and S(O) 2 CH 2 can be prepared by a reaction of the compounds wherein Z is SCH 2 using an oxidant such as sodium metaperiodide in a solvent such as methanol.
  • the compounds used in the present invention can be administered orally or parenterally such as intravenously or nasally.
  • they can be administered orally in the form such as tablets, dusting powders, granules, powders, capsules, solutions, emulsions or suspensions, each of which can be prepared according to conventional methods.
  • dosage forms for intravenous administration there are used aqueous or non-aqueous solutions, emulsions, suspensions or solid preparations to be dissolved in a solvent for injection immediately before use.
  • nasal administration can be performed by spraying quantitatively a solution or a powder (hard capsules) containing the drug into the nasal cavity by use of a dedicated nasal dropper or sprayer.
  • the compounds in the present invention can be formulated into the form of the inclusion compounds with ⁇ -, ⁇ - or ⁇ -cyclodextrin, or methylated cyclodextrin.
  • the dose is varied by the age, body weight, etc., but it generally is from 1 ng to 1 mg/day per adult.
  • the present invention makes it possible to provide a sleep-inducing preparation which is sufficiently effective and remarkably stable.
  • Fig. 1 is a drawing which shows a result of the sleep-inducing action by administration of Compound 32 according to Experiment 2
  • Fig. 2 is a drawing which shows a result of the sleep-inducing effect by administration of PGD 2 according to Experiment 2.
  • Test drug 1 a hard capsule preparation containing 1 mg of Compound 4 and 30 mg of calcium carbonate (light)
  • Test drug 2 a hard capsule preparation containing 1 mg of Compound 4 and 30 mg of calcium carbonate (heavy)
  • Test drug 3 a hard capsule preparation containing 1 mg of Compound 4 and 30 mg of sofalcone
  • the sleep-inducing actin was definitely observed in 2 monkeys out of 3 (6 monkeys out of 9) in a period of from 5 to 15 minutes after the nasal administration, followed by drowsy stages.
  • the vehicle-treated group was observed to take the weak sleep.
  • the significant sleep action was observed 30 - 75 minutes after the administration when compared with the group treated with vehicle (Fig. 1).
  • the significant sleep action was observed 45 minutes to 5 hours after the administration when compared with the group treated with vehicle (Fig 1).
  • the transient sleep action was observed in the group treated with 10 ⁇ g of PGD 2 /monkey 45 minutes after the administration (Fig. 2).
  • Brain wave was recorded according to the method described in the literature (H. ONOE, Proc. Natl. Acad. Sci., 1988, Vol. 185, p.4082).
  • the cerebrospinal fluid was identified by insertion of a spiral needle into the cerebellomedullary cistern from the occipital region under sevoflurane-inhalation anesthesia, after which the test drug (isotonic sodium chloride solution of Compound 32 sterilized through a Millipore filter) was cerebellomedullary-cisternally administered in the amount of 10 ⁇ g/0.1 ml/monkey.
  • test drug isotonic sodium chloride solution of Compound 32 sterilized through a Millipore filter
  • Brain wave (EEG) was continuously recorded by a data recorder using a telemetry system (UA-10, Data Sciences, Inc.) for 4 hours after the administration of the test substance, and the behaviors were observed by a video recording system.
  • the changes of sleep-wake stages (wake, non-REM sleep and REM sleep) with time were observed by the changes of brain wave, electromyogram and behavior.
  • the wake, non-REM sleep, REM sleep times, and the frequency of REM sleep were determined in a period of from 20 minutes to 240 minutes after the administration of the test substance, and results are shown in Table 2.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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EP99921249A 1998-05-25 1999-05-25 Sleep inducing agent comprising prostaglandin derivatives Expired - Lifetime EP1082961B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP14262298 1998-05-25
JP14262298 1998-05-25
PCT/JP1999/002723 WO1999061029A1 (fr) 1998-05-25 1999-05-25 Agent somnifere

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EP1082961A1 EP1082961A1 (en) 2001-03-14
EP1082961A4 EP1082961A4 (en) 2001-07-11
EP1082961B1 true EP1082961B1 (en) 2006-01-25

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EP99921247A Expired - Lifetime EP1083168B1 (en) 1998-05-25 1999-05-25 Prostaglandin derivative

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US (2) US6329539B1 (pt)
EP (2) EP1082961B1 (pt)
JP (3) JP4354644B2 (pt)
KR (2) KR100623941B1 (pt)
CN (2) CN1144588C (pt)
AT (2) ATE252555T1 (pt)
AU (2) AU742118B2 (pt)
CA (2) CA2334355C (pt)
DE (2) DE69912277T2 (pt)
DK (1) DK1083168T3 (pt)
ES (2) ES2211083T3 (pt)
HK (2) HK1037535A1 (pt)
PT (1) PT1083168E (pt)
WO (2) WO1999061419A1 (pt)

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MXPA01008955A (es) 1999-03-05 2002-04-24 Procter & Gamble Analogos de prostaglandinas selectivas de fp no saturadas de c16.
CA2389869A1 (en) 1999-11-24 2001-05-31 Taisho Pharmaceutical Co., Ltd. Preparation for nasal administration
US20020013294A1 (en) 2000-03-31 2002-01-31 Delong Mitchell Anthony Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US20020172693A1 (en) 2000-03-31 2002-11-21 Delong Michell Anthony Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
MXPA04002006A (es) 2001-08-31 2004-06-07 Sucampo Ag Analogos de prostagladina como abridor del canal de cloruro.
WO2003048140A1 (fr) * 2001-12-03 2003-06-12 Japan Tobacco Inc. Compose azole et utilisation medicinale de celui-ci
US20040266880A1 (en) * 2002-02-22 2004-12-30 Fumie Sato Antipruritics
EP1553083B1 (en) * 2002-07-12 2009-08-26 Taisho Pharmaceutical Co., Ltd Prostaglandin derivatives
US7737182B2 (en) * 2002-08-09 2010-06-15 Taisho Pharmaceutical Co., Ltd. Pharmaceuticals for xerosis
EP1527781B1 (en) * 2002-08-09 2008-07-23 Taisho Pharmaceutical Co., Ltd Antipruritic agent
US7037522B2 (en) * 2002-09-27 2006-05-02 Western Holdings, L.L.C. Nocturnal muscle enhancing composition and method
AU2003301900A1 (en) * 2002-11-13 2004-06-03 Fumie Sato Antipruritic drug
US20060270740A1 (en) * 2003-02-20 2006-11-30 Taisho Pharmaceutical Co., Ltd. And Fumie Sato Prostaglandin derivatives
WO2004089918A1 (ja) * 2003-04-09 2004-10-21 Japan Tobacco Inc. 複素芳香５員環化合物及びその医薬用途
JP5382898B2 (ja) * 2004-02-06 2014-01-08 大正製薬株式会社 乾皮症治療剤

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JPH07103096B2 (ja) 1987-01-28 1995-11-08 株式会社上野製薬応用研究所 プロスタグランジンｄ類およびそれを含む鎮静・睡眠剤
CA1322749C (en) 1987-01-28 1993-10-05 Ryuzo Ueno Prostaglandins of the d series, and tranquilizers and soporifics containing the same
DE4036140A1 (de) * 1990-11-09 1992-05-14 Schering Ag 9-halogen-11ss-hydroxy-prostaglandinderivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE69214953T2 (de) 1991-04-22 1997-02-20 Taiho Pharmaceutical Co Ltd Prostaglandin e1-analoge
JPH05117230A (ja) 1991-04-22 1993-05-14 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体
EP0652211A1 (en) * 1992-07-24 1995-05-10 Taisho Pharmaceutical Co. Ltd Prostaglandin derivative
JP3408835B2 (ja) 1993-03-23 2003-05-19 大正製薬株式会社 Ｅ型プロスタグランジン類の製造方法
JP3579448B2 (ja) * 1993-12-29 2004-10-20 大正製薬株式会社 プロスタグランジン誘導体、その塩およびその使用
JP3506485B2 (ja) * 1994-04-19 2004-03-15 大正製薬株式会社 プロスタグランジン誘導体
US5599838A (en) * 1996-02-23 1997-02-04 Taisho Pharmaceutical Co., Ltd. Prostaglandin derivatives

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CA2333038A1 (en) 1999-12-02
US6329539B1 (en) 2001-12-11
KR20010043596A (ko) 2001-05-25
ATE252555T1 (de) 2003-11-15
HK1037610A1 (en) 2002-11-08
AU742232B2 (en) 2001-12-20
CN1144588C (zh) 2004-04-07
CA2333038C (en) 2008-12-02
DE69929594D1 (de) 2006-04-13
CA2334355A1 (en) 1999-12-02
DK1083168T3 (da) 2003-12-15
KR20010043595A (ko) 2001-05-25
AU742118B2 (en) 2001-12-20
EP1082961A4 (en) 2001-07-11
WO1999061029A1 (fr) 1999-12-02
JP4354644B2 (ja) 2009-10-28
HK1037535A1 (en) 2002-11-08
CN1303292A (zh) 2001-07-11
CN1303370A (zh) 2001-07-11
KR100623941B1 (ko) 2006-09-13
ATE316378T1 (de) 2006-02-15
WO1999061419A1 (fr) 1999-12-02
DE69912277T2 (de) 2004-07-15
US6395786B1 (en) 2002-05-28
JP2000044477A (ja) 2000-02-15
EP1083168B1 (en) 2003-10-22
EP1082961A1 (en) 2001-03-14
ES2257860T3 (es) 2006-08-01
JP4409767B2 (ja) 2010-02-03
ES2211083T3 (es) 2004-07-01
EP1083168A4 (en) 2002-09-04
KR100570521B1 (ko) 2006-04-12
AU3851499A (en) 1999-12-13
CN1144783C (zh) 2004-04-07
DE69912277D1 (de) 2003-11-27
DE69929594T2 (de) 2006-12-07
EP1083168A1 (en) 2001-03-14
PT1083168E (pt) 2004-03-31
CA2334355C (en) 2009-01-27
AU3851299A (en) 1999-12-13

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